50-06-6 Usage
Uses
Used in Pharmaceutical Industry:
Phenobarbital is used as an anticonvulsant, sedative, and hypnotic for the treatment of epilepsy, chorea, and spastic paralysis. It is also a component of combined drugs such as valocordin and corvalol, which are used for their relaxant, soporific, and anticonvulsant activities.
Antiepileptic
Phenobarbital, also known as Rumina and Canaa, is white andglossy crystalline powder. Phenobarbital is a non- proprietary first- generation antiepileptic drug. Exposed to air at normal temperature, it is stable in nature, difficult to dissolve in water and insoluble in acid. It can be dissolved in ethanol, ether, acetone and other organic solvents. This product has sedative, hypnotic and anticonvulsant effects, and can resist epilepsy. It is effective for large epileptic seizures, localized seizures and status epilepticus. It also enhances the role of antipyretic analgesics, and can induce liver microsomal glucuronosyltransferase activity, promote bilirubin and glucuronic acid binding, reduce plasma bilirubin concentration, and treat neonatal cerebral nucleus jaundice. Figure 1 Structural formula of phenobarbital
Barbiturate drugs
Barbiturate: It is a type of tranquilizer that acts on the central nervous system and is a derivative of barbituric acid. Its application ranges from mild sedation to complete anaesthesia, and can also be used as antianxiety drugs, sleeping pills, and antispasmodic drugs. Long term use leads to addiction.
Physicochemical properties
Physical properties: barbiturates are usually white crystal or crystalline powder. Stable in the air. General slightly soluble or soluble in water, soluble in ethanol, ethyl ether, dissolved in chloroform.
Sodium salt is easy to dissolve in water and is difficult to dissolve in organic solvent.
Chemical properties: a. Faintly acidic: in the hexatomic ring of barbiturates, the 1,3- imidodicarbonic diamide group can occur ketone enol tautomerism and ionize in aqueous solution. Therefore, barbiturate is weak acidity, and pKa is 7.3 to 8.4.?
b.Easy hydrolysis: the imidodicarbonic diamide group can be hydrolyzed under the alkaline condition and release ammonia gas.?
c. Reaction with heavy metal ions:If the silver nitrate is added to the Barbital sodium carbonate solution,it will generate white insoluble disilver salt; With pyridine and copper sulfate solution, it will generate blue violet complex for identification and measurement of content. The action mechanism of Barbiturate drug.Barbiturates act on the synaptic transmission process of the netting excitatory system, block the network structure and activate the system, reduce the excitability of the cortical cells, resulting in stabilization, hypnotic and anticonvulsant effects. This effect is mainly seen in the synapses of GABA neurotransmitters. It enhances the GABA mediated Cl- inflow and weakens the depolarization mediated by glutamate. Barbiturates increase the Cl- internal flow by prolonging the opening time of the chloride channel, causing hyperpolarization. At higher concentrations, it inhibits the Ca2+ dependent action potential, inhibits the release of Ca2+ dependent transmitters, and presents a quasi GABA effect. That is, it can also increase the Cl- inflow directly when there is no GABA.
Pharmacological action
This product is a sedative hypnotic and anticonvulsant and it is atypical representative of long-acting barbiturate. The inhibitory effect on the central nervous system increases with the dose. It is characterized by sedative, hypnotic, anticonvulsant and antiepileptic.
Large doses have obvious inhibition on the cardiovascular system and respiratory system.Excessive use can paralyze the medulla of the respiratory center and thus cause death. In the electrophysiological experiment in vitro, it is found that phenobarbital makes the chloride channels of the nerve cells open and the cells are polarised, which is similar to the role of gamma aminobutyric acid (GABA).The treatment concentration of phenobarbital can reduce the excitatory effect of glutamate and strengthen the inhibitory effect of gamma aminobutyric acid, It inhibits the transmission of single synapses and multiple synapses in the central nervous system, and inhibits the high frequency discharge of the epileptic focus and its diffusion around the central nervous system.
Pharmacokinetics
After oral administration, it is absorbed completely but slowly in the digestive tract. It will take effect 0.5 to 1 hours after injection, and the concentration of blood drug reaches the peak value after 2~18 hours. After absorption, the plasma protein binding rate is about 40% (20% ~ 45%), and the apparent volume is 0.5 ~ 0.9L/kg.The concentration is highest in the brain tissue. The largest amount of medicine is in the skeletal muscle. It can pass through the placenta. Its effective blood concentration is about 10~40 g/ml, and it will have toxic reaction when the blood concentration is more than 40μg/ml. The adult half-life (t1/2) is about 50~144 hours, the child is about 40~70 hours, and the half-life (t1/2) will be prolonged if the liver and kidney function worse. About 48% ~ 65% of phenobarbital is metabolized in the liver and converted to phenobarbital. This product is a liver enzyme inducer to improve the activity of the enzyme, not only to accelerate the metabolism of its own, but also to accelerate the metabolism of other drugs.Most of this product is combined with glucuronic acid or sulfate, excreted by the kidneys.There are 27% to 50% of the prototypes excreted from the kidneys.It can pass through the placenta and secrete human milk.
Indications
It is mainly used for the treatment of anxiety, insomnia (used for short sleep time, early awakening), epilepsy and dyskinesia.
It is an important drug for the treatment of major epileptic seizures and localized seizures.It can also be used as a drug for anti hyperbilirubinemia and before anesthesia.Injection is used for the treatment of epilepsy. It is effective for systemic and partial seizures. It is generally used when phenytoin, carbamazepine and valproate are ineffective. It can also be used for other diseases caused by convulsions and before anesthesia.
Indications
Phenobarbital can reduce cholestatic pruritus, possibly
by enhancing hepatic microsomal function. Phenobarbital is sedating and
may interfere with the metabolism of many drugs.
Adverse reaction
The most common adverse reaction for antiepileptic seizures is sedation. But as the course continues, its sedative effect gradually becomes unobvious.
It may cause subtle emotional changes, and a defect in cognition and memory.In the long-term medication, occasionally folic acid deficiency and hypocalcemia can be seen.
Megaloblastic anemia and osteomalacia are rarely seen.
In large doses, nystagmus, ataxia, and severe respiratory depression can be produced.1% to 3% of the patients using this product have skin reactions.The most common sights are rashes. Exfoliative dermatitis and polymorphous erythema or Stevens-Johnson syndrome may occur in severe cases, and toxic epidermal necrosis is extremely rare.
There are reports of hepatitis and liver dysfunction.
Drug dependence may occur for a long time drug taking.It is easy to withdrawal syndrome ?after stopping drug use.
Precaution
People allergic to barbiturate may also be allergic to this product.For antiepileptic drug application, it may take 10~30 days to reach the maximum effect. It is necessary to calculate the amount of medicine by weight. If possible, it is necessary to determine the concentration of blood drug regularly to reach the maximum effect.
In patients suffer from liver dysfunction, the dosage should start from a small amount.Long-term use of drugs can produce mental or physical dependence on drugs. The withdrawal of drugs should be gradually reduced, so as to avoid the withdrawal symptoms.
Combined with other central suppressor drugs, it has a synergistic inhibitory effect on the center, and should be paid attention to.Be cautious in the following cases: minimal brain dysfunction, hypotension, hypertension, anemia, hypothyroidism and adrenal insufficiency, liver and kidney function damage, aerial, driver, fine and dangerous type operators.
This medicine may pass through the placenta,Long term use in pregnancy can cause dependence and drug withdrawal syndrome.
Neonatal hemorrhage may be caused by reduced vitamin K content.If it is used in the late pregnancy or childbirth, because the fetal liver function is not mature, it can cause the respiratory depression of the newborn (especially the premature infant).It may have a teratogenic effect on the fetus. FDA classifies it as grade D for the safety of pregnancy. The application of it during lactation may cause the suppression of the central nervous system in the baby.
It may cause abnormal excitement, and attention should be paid to it.
The usual dose of this drug can cause excitement, insanity or depression. Therefore, the dosage should be small.
Drug interaction
1. This product is a liver enzyme inducer, which can improve the activity of the enzyme. Long term use not only accelerates its metabolism, but also accelerates the metabolism of other drugs. Before using anaesthesia, such as halothane, enflurane, methoxane etc., if the barbiturate has been taken for a long time, it can increase the metabolites of the anesthetic and increase the risk of liver toxicity. When barbiturates are used simultaneously with ketamine, especially large doses of intravenous administration, it can increase the risk of lowering blood pressure and breathing inhibition.
2. When combined with oral anticoagulants, it can reduce the effect of the latter.
3. Its combined use with oral contraceptives can reduce the reliability of the contraceptive. Its combination use with estrogen and estrogen reduces the effect of estrogen.It can reduce the effects of these drugs when it is combined with corticosteroids, digitalis (including digoxin), oxytetracycline, or tricyclic antidepressants.?
4.In combination with cyclophosphamide, it can theoretically increase the alkylation of cyclophosphamide metabolites, but the clinical significance is not clear.
5. When combined with quinidine, it attenuates the effect of quinidineby increasing the metabolism of quinidine.It is combined with a calcium channel blocker, causing a drop in blood pressure. When combined with fluperbutanol for the treatment of epilepsy, it can cause changes in the form of epileptic seizures and doses need to be adjusted.
6. When combined with phenothiazine and tetracyclic antidepressants, it can reduce the seizure threshold and increase the inhibitory effect. Combined with ibuprofen it can reduce or shorten the half-life and reduce the intensity of action.
Interactions
With AEDs
Both primidone and its major metabolite phenobarbital are metabolized by, and also induce, liver enzyme activity (especially the CYP 450 3A4 enzyme system). There are a number of interactions which are potentially clinically significant.
Phenobarbital and primidone plasma concentrations are increased by oxcarbazepine, phenytoin and valproate.
Vigabatrin possibly decreases phenobarbital and primidone plasma concentrations.
Phenobarbital and primidone therapy may also lead to altered pharmacokinetics in concomitantly administered AEDs, whose metabolism may be increased, and lead to lowered plasma levels and/ or a shorter halflife: carbamazepine, ethosuximide, lamotrigine, oxcarbazepine, phenytoin, valproate, tiagabine, topiramate, zonisamide.
With other drugs
Agents which inhibit the CYP 450 3A4 enzyme system, such as chloramphenicol, nelfinavir, and metronidazole may result in increased plasma levels of concomitantly administered primidone and its metabolite phenobarbital.
In addition, St John’s Wort induces the CYP450 enzyme system and may result in a reduction of plasma levels of concomitantly administered primidone and of its metabolite phenobarbital.
Phenobarbital and primidone therapy may also lead to altered pharmacokinetics in concomitantly administered drugs, whose metabolism may be increased, and lead to lowered plasma levels and/ or a shorter half- life. These drugs include androgens, beta- antagonists, ciclosporin, clozapine, chloramphenicol, corticosteroids/ glucocorticosteroids, cyclophosphamide, dicoumarins, digitoxin, doxycycline, etoposide, granisetron, losartan, methadone, metronidazole, mianserin, montelukast, nelfinavir, nimodipine, oral contraceptives, quinidine, rocuronium, theophyllines, tricyclic antidepressants, vecuronium, and warfarin.
The central nervous system (CNS) depressant effect of phenobarbital and primidone is additive to those of other CNS depressants such as opiates.
With alcohol/food
Concurrent administration with alcohol may lead to an additive CNS depressant effect and there are no specific foods that must be excluded from diet when taking phenobarbital or primidone.
Special populations
Hepatic impairment
Reduce dose as it may precipitate coma (avoid in severe impairment).
Renal impairment
Use with caution.
Pregnancy
Phenobarbital and primidone therapy in pregnant women with epilepsy present a risk to the foetus in terms of major and minor congenital defects, such as congenital craniofacial, heart, and digital abnormalities, as well as cleft lip and palate.
In case of treatment during pregnancy, the dose of phenobarbital and primidone should be monitored carefully and adjustments made on a clinical basis.
Phenobarbital and primidone readily cross the placenta following oral administration and are distributed throughout foetal tissue, the highest concentrations being found in the placenta, foetal liver and brain. Adverse effects on neurobehavioural development and withdrawal symptoms have been reported in the newly born whose mothers have received phenobarbital or primidone during late pregnancy
Phenobarbital and primidone are excreted into breastmilk and there is a small risk of neonatal sedation. During breastfeeding, the baby should be monitored for sedation, although breastfeeding is not advisable.
Behavioural and cognitive effects in patients with epilepsy
Patients taking phenobarbital have been shown to have a high prevalence of major depressive disorder and suicidal ideation. A long history of exposure to barbiturates may carry the greatest risk of depression, particularly in patients taking polytherapy and patients with a personal or family history of affective disorders. Similarly to benzodiazepines, barbiturates can also induce a paradoxycal syndrome characterized by insomnia, hyperactivity, impulsiveness and aggressiveness (especially in patients with learning disability). Barbiturates are more frequently associated with adverse cognitive side effects than most other AEDs. The spectrum of cognitive problems reported by patients with epilepsy taking phenobarbital encompasses attention, memory, and language.
Psychiatric use
Barbiturates have no approved indications in psychiatry. Off-label uses have previously included sedative-hypnotic withdrawal and alcohol- withdrawal (as alternative to benzodiazepines).
Originator
Phenobarbital ,Inter-Chemical Ltd.
Manufacturing Process
528 g phenylethyl malonic diethyl ester is dissolved in 500 ml of absolute alcohol. There is then added 140 g urea to the mixture. To this mixture is then added a solution of 57.5 g sodium in 1000 ml absolute alcohol, at such rate that one-half the solution is added during the first hour, a quarter the second hour; an eighth the third hour, and the final eighth during the 4 hours. Then the alcohol is distilled from the reaction mixture. When the alcohol has all been removed, 250 ml xylol is added to the mixture. The reaction mixture is cooled to room temperature and 3 L of water added. The xylene layer was separated and the water solution washed with another 200 ml portion of xylene There is then added to the water solution a 10% excess of a 50% by weight solution of sulfuric acid. The phenobarbital is precipitated as nearly white fluffy crystals, which are filtered off. When dried, they showed 100% phenobarbital by titration. This product may be purified by recrystallization. The unreacted ester in the xylene solution was recovered by distilling off the xylene, and then the phenylethyl malonic ester.
Therapeutic Function
Anticonvulsant, Antiepileptic, Hypnotic, Sedative
World Health Organization (WHO)
Phenobarbital is a long-acting barbiturate which is controlled
under Schedule IV of the 1971 Convention on Psychotropic Substances.
Phenobarbital is of value in the treatment of epilepsy and preparations for such
use are included in the WHO Model List of Essential Drugs. See also WHO
comment for barbiturates.
(Reference: (UNCPS4) United Nations Convention on Psychotropic Substances (IV),
, , 1971)
Air & Water Reactions
Sensitive to hydrolysis. Alkaline solutions react more rapidly than acidic solutions. At pH 7 and 176°F, has a half life of 74 hours. Insoluble in water.
Reactivity Profile
Phenobarbital is also sensitive to prolonged exposure to light. Incompatible with strong oxidizing agents. Forms a complex of reduced solubility with macrogol 4000. Able to form metal derivatives .
Fire Hazard
Phenobarbital is combustible.
Clinical Use
Antiepileptic
Safety Profile
Confirmed carcinogen
with experimental carcinogenic,
neoplastigenic, tumorigenic, and teratogenic
data. A human poison by ingestion. An
experimental poison by ingestion,
intraperitoneal, subcutaneous, intravenous,
and rectal routes. Human systemic effects by
ingestion: somnolence, motor activity
changes, pulmonary changes, allergc
dermatitis, and fever. Human reproductive
effects by ingestion: drug dependence and
other postnatal measures or effects. Human
teratogenic effects include developmental abnormalities of the central nervous system,
body wall, musculoskeletal, respiratory,
gastrointestinal, and urogenital systems.
Experimental reproductive effects. Human
mutation data reported. Used as a drug in
the treatment of epilepsy, and as a hypnotic
and sedative. When heated to
decomposition it emits toxic fumes of NOx.See also BARBITURATES.
Synthesis
Phenobarbital, 5-ethyl-5-phenylbarbituric acid or 5-ethyl-5-phenylhexahydropyrimindin-2,4,6-trione (4.1.4), has been synthesized in several different ways [1–4].
There is no major difference between them. The first method consists of ethanolysis
of benzyl cyanide in the presence of acid, giving phenylacetic acid ethyl ether, the
methylene group of which undergoes acylation using the diethyloxalate, giving diethyl
ester of phenyloxobutandioic acid (4.1.1), which upon heating easily loses carbon oxide
and turns into phenylmalonic ester (4.1.2). Alkylation of the obtained product using
ethylbromide in the presence of sodium ethoxide leads to the formation of α-phenyl-α-
ethylmalonic ester (4.1.3), the condensation of which with urea gives phenobarbital
(4.1.4) [1].Another method of phenobarbital synthesis starts with condensation of benzyl cyanide with
diethylcarbonate in the presence of sodium ethoxide to give α-phenylcyanoacetic ester
(4.1.5). Alkylation of the ester (4.1.5) using ethylbromide gives α-phenyl-α-ethylcyanoacetic ester (4.1.6), which is further converted into the 4-iminoderivative (4.1.7). Acidic hydrolysis
of the resulting product gives phenobarbital (4.1.4) [2].
Drug interactions
Potentially hazardous interactions with other drugs
Aminophylline and theophylline: metabolism of
aminophylline and theophylline increased, reduced
effect.
Anthelmintics: concentration of albendazole and
praziquantel reduced. Anti-arrhythmics: reduced concentration of
disopyramide; possibly reduced concentration of
dronedarone - avoid; possibly increases metabolism
of propafenone.
Antibacterials: reduced concentration of
chloramphenicol, doxycycline, metronidazole,
telithromycin and rifampicin - avoid with
telithromycin.
Anticoagulants: increased metabolism of coumarins
(reduced effect); concentration of apixaban, edoxaban
and rivaroxaban reduced.
Antidepressants: antagonise anticonvulsant effect;
reduces concentration of paroxetine, reboxetine,
mianserin and tricyclics; concentration reduced by St
John’s wort - avoid.
Antiepileptics: concentration increased by
oxcarbazepine, phenytoin, stripentol and valproate
and possibly carbamazepine, also active metabolite of
oxcarbazepine reduced and valproate concentration
reduced, concentration of fosphenytoin and
phenytoin usually reduced but can also be increased;
concentration of ethosuximide, rufinamide and
topiramate possibly reduced; concentration of
lamotrigine, tiagabine and zonisamide reduced.
Antifungals: possibly reduced concentration of
itraconazole, isavuconazole, posaconazole and
voriconazole - avoid with voriconazole; reduced
absorption of griseofulvin (reduced effect).
Antimalarials: avoid with piperaquine with
artenimol; anticonvulsant effect antagonised by
mefloquine.
Antimuscarinics: possibly reduces active metabolite
of fesoterodine - avoid.
Antipsychotics: antagonise anticonvulsant effect;
metabolism of haloperidol increased; possibly
reduces aripiprazole concentration - increase
aripiprazole dose; concentration of both drugs
reduced with chlorpromazine; possibly reduces
clozapine concentration; possibly reduces lurasidone
concentration - avoid.
Antivirals: concentration of abacavir, boceprevir,
darunavir, fosamprenavir, indinavir, lopinavir,
rilpivirine and saquinavir possibly reduced; avoid
with boceprevir and rilpivirine; possibly reduces
daclatasvir, dasabuvir, ombitasvir, paritaprevir
and simeprevir concentration - avoid; avoid with
elvitegravir, etravirine, ledipasvir, sofosbuvir and
telaprevir; possibly reduces concentration of
dolutegravir.
Apremilast: possibly reduces concentration of
apremilast - avoid. Bile acids: avoid with cholic acid.
Calcium-channel blockers: effects of calcium-channel
blockers probably reduced - avoid with isradipine
and nimodipine.
Cannabis extract: possibly reduces concentration of
cannabis extract - avoid.
Ciclosporin: reduced ciclosporin levels.
Cobicistat: possibly reduces concentration of
cobicistat - avoid.
Corticosteroids: metabolism of corticosteroids
accelerated, reduced effect.
Cytotoxics: possibly reduced concentration
of axitinib, increase axitinib dose; possibly
reduced concentration of bortezomib, bosutinib,
cabozantinib, ceritinib, crizotinib, dasatinib,
ponatinib and vandetanib - avoid; avoid with
cabazitaxel, ceritinib, dabrafenib, gefitinib, olaparib
and panobinostat; concentration of irinotecan and
its active metabolite and possibly etoposide reduced;
possible increased hypersensitivity reactions with
procarbazine.
Diuretics: concentration of eplerenone reduced -
avoid; increased risk of osteomalacia with carbonic
anhydrase inhibitors.
Guanfacine: concentration of guanfacine possibly
reduced - increase dose of guanfacine.
Hormone antagonists: possibly reduced
concentration of abiraterone - avoid; metabolism of
toremifene accelerated.
Ivacaftor: possibly reduced concentration of ivacaftor
- avoid.
Oestrogens and progestogens: metabolism
accelerated, reduced contraceptive effect. Orlistat: possibly increased risk of convulsions.
Sodium oxybate: enhanced effects of sodium oxybate
- avoid.
Tacrolimus: concentration of tacrolimus reduced.
Ulipristal: contraceptive effect reduced - avoid.
Metabolism
Partly metabolised in the liver.
25% of a dose is excreted in the urine unchanged at
normal urinary pH.
Check Digit Verification of cas no
The CAS Registry Mumber 50-06-6 includes 5 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 2 digits, 5 and 0 respectively; the second part has 2 digits, 0 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 50-06:
(4*5)+(3*0)+(2*0)+(1*6)=26
26 % 10 = 6
So 50-06-6 is a valid CAS Registry Number.
InChI:InChI=1/C12H12N2O3/c1-2-12(8-6-4-3-5-7-8)9(15)13-11(17)14-10(12)16/h3-7H,2H2,1H3,(H2,13,14,15,16,17)
50-06-6Relevant articles and documents
Preparative microfluidic electrosynthesis of drug metabolites
Stalder, Romain,Roth, Gregory P.
supporting information, p. 1119 - 1123 (2013/12/04)
In vivo, a drug molecule undergoes its first chemical transformation within the liver via CYP450-catalyzed oxidation. The chemical outcome of the first pass hepatic oxidation is key information to any drug development process. Electrochemistry can be used to simulate CYP450 oxidation, yet it is often confined to the analytical scale, hampering product isolation and full characterization. In an effort to replicate hepatic oxidations, while retaining high throughput at the preparative scale, microfluidic technology and electrochemistry are combined in this study by using a microfluidic electrochemical cell. Several commercial drugs were subjected to continuous-flow electrolysis. They were chosen for their various chemical reactivity: their metabolites in vivo are generated via aromatic hydroxylation, alkyl oxidation, glutathione conjugation, or sulfoxidation. It is demonstrated that such metabolites can be synthesized by flow electrolysis at the 10 to 100 mg scale, and the purified products are fully characterized.
Fluorescence immunoassays using fluorescent dyes free of aggregation and serum binding
-
, (2008/06/13)
Fluorescence immunoassays methods are provided which use fluorescent dyes which are free of aggregation and serum binding. Such immunoassay methods are thus, particularly useful for the assay of biological fluids, such as serum, plasma, whole blood and urine.
Water dispersion containing ultrafine particles of organic compounds
-
, (2008/06/13)
A water-dispersible condensate of water-insoluble ultrafine particles of medicine or hormones having a particle size of at largest 4 μm prepared by the steps of heating the medicine or hormone in a vacuum vessel at a temperature of 30° C. higher than the boiling point and at a pressure between 0.01 Torr and 10 Torr to evaporate the medicine or hormone and condensing the medicine or hormone on a recovery plate to obtain the condensate.
New chemical aspects of primidone metabolism
Lafont,Cave,Menager,Miocque
, p. 61 - 66 (2007/10/02)
Primidone is metabolized either into phenylethylmalondiamide or phenobarbital. 2-Hydroxyprimidone was synthesized and tested as a potential intermediate common to these two biodegradation pathways in dogs as well as in vitro. On the other hand, the mechanism of the formation of α-phenyl-γ-butyrolactone during intoxication was investigated and the role of precursor played by the phenobarbital generated in vivo was shown.
Anticonvulsants in epileptic fowl
Johnson,Davis
, p. 1753 - 1757 (2007/10/02)
The high seizure susceptibility in epileptic fowl is an autosomal recessive trait characterized in homozygotes by seizures that occur spontaneously and in response to photic stimulation or hyperthermia. Both of the latter stimuli can be used to evoke seizures in drug studies. Epileptic fowl have abnormal inter-ictal EEG activity. When exposed to photic stimulation spiking is apparent on the EEG at seizure onset. Phenobarbital, primidone, phenytoin, and valproic acid reduce seizure susceptibility at plasma concentrations approximating those used to control generalized and focal cortical tonic-clonic seizures in humans. Carbamazepine and the benzodiazepines also reduce seizure susceptibility. These data include that epileptic fowl provide a useful model for generalized and focal cortical tonic-clonic epilepsies. Ethosuximide was inactive in epileptic fowl. However, trimethadione had anticonvulsant activity indicating that this model is only relatively specific for the above seizure types. When seizures were evoked by hyperthermia phenobarbital but not phenytoin or valproate reduced seizure susceptibility. GABA (γ-aminobutyric acid), AOAA (amino-oxyacetic acid) and THPO (4,5,6,7-tetrahydroisoxazolo[4,5-c] pyridin-3-ole, a glial specific inhibitor of GABA uptake) all have anticonvulsant activity against seizures evoked by photic stimulation in young chicks. These data indicate that this model may be particularly useful for studies of the anticonvulsant activity of compounds designed to enhance GABAergic transmission.
The Chemistry of Aryllead(IV) Tricarboxylates. Reaction with Derivatives of Malonic Acid: New Routes to α-Aryl Carboxylic Acids and Arylated Barbituric Acid Derivatives
Kopinski, Richard P.,Pinhey, John T.,Rowe, Bruce A.
, p. 1245 - 1254 (2007/10/02)
Derivatives of 2,2-dimethyl-1,3-dioxan-4,6-dione (Meldrum's acid) and the sodium salts of substituted malonic esters undergo electrophilic C-arylation in high yield with aryllead triacetates, thus providing new routes to α-arylalkanoic acids.Syntheses of the antiflammatory compound 2-(p-isobutylphenyl)propanoic acid (Ibuprofen) have been carried out to demonstrate the method.The arylation reaction has been extended to 5-ethylbarbituric acid and to barbituric acid itself, which affords the 5,5-diarylated derivatives in good yield.A study of the effect of some tertiary bases on the reaction of p-methoxyphenyllead triacetate with the 5-isopropyl derivative of Meldrum's acid has shown that replacement of pyridine by 2,2'-bipyridyl results in an increase in yield and reaction rate, while a further marked improvement occurs in the presence of 1,10-phenanthroline.
THE REACTION OF t-BUTYL HYPOCHLORITE WITH THIOCARBONYL COMPOUND - A CONVENIENT METHOD FOR THE TRANSFORMATION
El-Wassimy, M.T.M.,Jorgensen, K.A.,Lawesson, S.-O.
, p. 1729 - 1734 (2007/10/02)
The reaction of t-butyl hypochlorite with different thiocarbonyl compounds has been studied.Primary thioamides 1a-c give 1,2,4-thiadiazole derivatives.N-Phenylthiourea 4a gives 5-imino-4-phenyl-3-phenylamino-4,5-dihydro-1,2,4-thiadiazoline 15.Secondary and tertiary thioamides 2a-d, N-methyl-2-thiopyrrolidinone 3, N,N'-dicyclohexylthiourea 4b, N,N,N'-trimethylthiourea 4c, 5-ethyl-5-phenylthiobarbituric acid 5, xanthione 7a, Mischler's thioketone 7b, thiocoumarin 8, O-ethylthiobenzoate 9, O,O-diphenylthiocarbonate 10, di-p-tolyl and o-phenylene trithiocarbonates 11 and 12 have all afforded the oxigen analogues.N,N-Dimethyl-S-phenyldithiocarbonate 6 produces a mixture of di-, tri-, and tetrasulfides.A mechanism for the transformation is suggested in accordance with the Hard and Soft Acids and Bases (HSAB) principle.
HYDROLYSIS OF BARBITURIC ACID DERIVATIVES. PART V. HYDROLYSIS OF 1-BENZOYL-5-ETHYL-5-PHENYLBARBITURIC ACID
Paluchowska, Maria,Ekiert, Leszek,Jochym, Krystyna,Bojarski, Jacek
, p. 799 - 807 (2007/10/02)
The pathways of hydrolytic degradation of 1-benzoyl-5-ethyl-5-phenylbarbituric acid have been investigated.The profiles of log k - pH of hydrolyses of 1-benzoyl-5-ethyl-5-phenylbarbituric acid and the main hydrolytic product i.e. 1-benzoyl-3-(2-phenylbutyryl)urea have been determined and discussed.
THE =C=S -> =C=O TRANSFORMATION USING THE SOFT NO(+)-SPECIES
Joergensen, K. A.,Ghattas, A.-B.A.G.,Lawesson, S.-O.
, p. 1163 - 1168 (2007/10/02)
The reaction of NaNO2 in acidic solution with thiocarbonyl compounds has been studied.Secondary- and tertiary thioamides, 1-benzyl-hexahydro-2H-azepine-2-thione, 5-ethyl-5-phenyl thiobarbituric acid, certain thiourea derivatives, 2H-1-benzopyran-2-thione, O,O-diphenyl-thiocarbonic ester, O,S-diphenyl-dithiocarbonic ester, N,N-dimethyl-S-phenyl-dithiocarbamatic ester, N-ethyl-N-phenyl-O-ethyl-thiocarbamatic ester are all converted into the corresponding carbonyl-analogues. 4,4'-Bis(dimethylamino)-thiobenzophenone (Michler's thioketone) gives 3-nitro-4,4'-bis(dimethylamino)-benzophenone at room temperature.At (-10 deg C)-(-5 deg C) the expected oxo compound is obtained as the main product together with 4-(N-nitroso-methylamino)-4'-(dimethylamino)-benzophenone.
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